Pharmaceutical Formulations

Abstract

A pharmaceutical formulation for delivery in aerosol or spray form, comprising a liquefied propellant gas, a solid particulate pharmaceutically active agent and a dispersing agent, wherein the dispersing agent is fused to the surface of particles of the pharmaceutically active agent.

1 . A pharmaceutical formulation for delivery in aerosol or spray form, comprising a liquefied propellant gas, a solid particulate pharmaceutically active agent and a dispersing agent, wherein the dispersing agent is fused to the surface of particles of the pharmaceutically active agent. 
     
     
         2 . A pharmaceutical formulation as claimed in  claim 1 , wherein the fused dispersing agent and pharmaceutically active agent form solid composite particles. 
     
     
         3 . A pharmaceutical formulation as claimed in  claim 1 , wherein said particles are suspended or suspendable in the liquefied propellant gas. 
     
     
         4 . A pharmaceutical formulation as claimed in  claim 1 , wherein the particles each comprise a particle of the pharmaceutically active agent at least partially coated with the dispersing agent. 
     
     
         5 . A pharmaceutical formulation as claimed in  claim 4 , wherein the dispersing agent forms an at least partial coating or shell around each of said particles of pharmaceutically active agent; said shell or coating covering at least 50, 70, 80, 90 or 95% of the surface area of the pharmaceutically active agent. 
     
     
         6 . A pharmaceutical formulation as claimed in  claim 5 , wherein the coating or shell of dispersing agent formed around the particles of pharmaceutically active agent has a mean thickness of 1, 0.5 or 0.2 μm or less. 
     
     
         7 . A pharmaceutical formulation as claimed in  claim 1  substantially free of CFC. 
     
     
         8 . A pharmaceutical formulation as claimed in  claim 1  that includes less than 3, 2, 1, 0.5, 0.1, 0.01 or 0.001%, or is substantially free of polar co-solvent. 
     
     
         9 . A pharmaceutical formulation as claimed in  claim 1  that includes less than 3, 2, 1, 0.5, 0.1, 0.01 or 0.001%, or is substantially free of co-solvent. 
     
     
         10 . A pharmaceutical formulation as claimed in  claim 1  that includes less than 3, 2, 1, 0.5, 0.1, 0.01 or 0.001%, or is substantially free of dissolved dispersing agent. 
     
     
         11 . A pharmaceutical formulation as claimed in  claim 1  consisting essentially of liquefied propellant gas and composite particles that comprise, pharmaceutically active agent and dispersing agent. 
     
     
         12 . A pharmaceutical formulation as claimed in  claim 1 , wherein the particles of fused pharmaceutically active agent and dispersing agent have an MMAD of between 0.1 and 100 μm. 
     
     
         13 . A pharmaceutical formulation as claimed in  claim 1 , wherein the particles of fused pharmaceutically active agent and dispersing agent have an MMAD of up to about 10 μm. 
     
     
         14 . A pharmaceutical formulation as claimed in  claim 1 , wherein the particles of fused pharmaceutically active agent and dispersing agent have an MMAD more than about 10 μm. 
     
     
         15 . A method for preparing a pharmaceutical formulation as claimed in  claim 1  comprising fusing the dispersing agent to the surface of particles of a solid particulate pharmaceutically active agent and admixing the solid particulate pharmaceutically active agent and dispersing agent with a liquefied propellant gas. 
     
     
         16 . A method as claimed in  claim 15 , wherein the liquefied propellant gas is admixed with the dispersing agent and particulate pharmaceutically active agent before, during and/or after the dispersing agent is fused to the particulate pharmaceutically active agent. 
     
     
         17 . A method as claimed in  claim 15 , wherein, the dispersing agent is fused to the surface of solid particles of pharmaceutically active agent by a method comprising bringing solid dispersing agent into contact with the particles of pharmaceutically active agent, and applying sufficient mechanical energy to contacting dispersing agent and particles of pharmaceutically active agent to cause fusion between them. 
     
     
         18 . A method as claimed in  claim 15 , wherein the dispersing agent is fused to the surface of the particles of pharmaceutically active agent to form solid composite particles. 
     
     
         19 . A method as claimed in  claim 18 , wherein each composite particle comprises a particle of the pharmaceutically active agent at least partially coated with the dispersing agent, which can be suspended in the liquefied propellant gas. 
     
     
         20 . A method as claimed in  claim 15 , wherein the mechanical energy is applied to a mixture of dispersing agent and active agent particles. 
     
     
         21 . A method as claimed in  claim 15 , wherein the mechanical energy is applied to a dry mixture of dispersing agent and active agent particles. 
     
     
         22 . A method as claimed in  claim 15 , wherein the mechanical energy is provided in the form of simultaneous compression and sheer forces applied to the contacting dispersing agent and active agent particles. 
     
     
         23 . A method as claimed in  claim 15 , wherein the dispersing agent is softer and/or more malleable than the pharmaceutically active agent within the temperature range at which said method is carried out. 
     
     
         24 . A method as claimed in  claim 15 , wherein the dispersing agent is softer and/or more malleable than the pharmaceutically active agent at a temperature in the range of 20-80° C. 
     
     
         25 . A pharmaceutical formulation as claimed in  claim 1 , wherein the dispersing agent is sufficiently soft and malleable, relative to the pharmaceutically active agent, such that it can be deformed, spread across and fused to the surfaces of the pharmaceutically active agent particles by the application of mechanical energy to contacting dispersing agent and particles of pharmaceutically active agent. 
     
     
         26 . A method as claimed in  claim 20 , wherein sufficient mechanical energy is applied to contacting particles of dispersing agent and pharmaceutically active agent to cause the dispersing agent particles to soften and/or distort such that the dispersing agent spreads across to at least partially coat the surfaces of the pharmaceutically active agent particles. 
     
     
         27 . A method as claimed in  claim 15 , wherein the particles of dispersing agent are smaller than the particles of pharmaceutically active agent and each of the composite particles comprises a plurality of dispersing agent particles fused to the surface of a particle of pharmaceutically active agent. 
     
     
         28 . A method as claimed in  claim 15 , wherein MMAD of the particles of active agent is between 0.1 and 100μ and the MMAD of the dispersing agent particles does not exceed 1 μm. 
     
     
         29 . A method as claimed in  claim 15 , wherein the ratio of the MMAD of the dispersing agent particles to the MMAD of the pharmaceutically active agent particles is 1:10 or more. 
     
     
         30 . A pharmaceutical formulation, prepared or preparable by a method as claimed in  claim 15 . 
     
     
         31 . A pharmaceutical formulation as claimed in  claim 1 , wherein the bond between the dispersing agent and the active agent is physical. 
     
     
         32 . A pharmaceutical formulation as claimed in  claim 31 , wherein the bond between the dispersing agent and the active agent involves physisorption of the dispersing agent by the pharmaceutically active agent and/or vice versa. 
     
     
         33 . A formulation as claimed in  claim 1 , wherein the dispersing agent is substantially insoluble in the liquefied propellant gas. 
     
     
         34 . A formulation as claimed in  claim 1 , wherein the dispersing agent reduces the surface free energy of the particles of pharmaceutically active agent. 
     
     
         35 . A formulation as claimed in  claim 1 , wherein the dispersing agent has a molecular weight of at least about 5500 or 6000. 
     
     
         36 . A formulation as claimed in  claim 1 , wherein the composite particles comprise less than 60% by weight dispersing agent. 
     
     
         37 . A formulation as claimed in  claim 1 , wherein the composite particles comprise 40-0.25, 30-0.5, 20-2, 10-2 or 8-3% by weight dispersing agent. 
     
     
         38 . A formulation as claimed in  claim 1 , wherein the dispersing agent is an anti-adherent material. 
     
     
         39 . A formulation as claimed in  claim 1 , wherein the dispersing agent comprises one or more amino acid, amino acid derivative, peptide, peptide derivative, metal stearate, metal palmitate, surface active agent, film forming agent, fatty acid, fatty acid derivative, lipid, lipid like material, lecithin, or phospholipid. 
     
     
         40 . A formulation as claimed in  claim 1 , wherein the dispersing agent comprises magnesium stearate. 
     
     
         41 . A formulation as claimed in  claim 1 , wherein the propellant comprises an HFA, or mixture of HFAs. 
     
     
         42 . A formulation as claimed in  claim 41 , wherein the HFA is HFA-134a or HFA-227. 
     
     
         43 . A formulation as claimed in  claim 1 , wherein the pharmaceutically active agent is one or more of: a steroid, a bronchodilator such as a β 2 -agonist, an antimuscarinic or a xanthine; a nitrate; an antihistamine; an antiinflammatory agent; an anticholinergic agent; a leukotriene receptor antagonist; an anti-allergic; an anti-emetic; a hormonal drug (including a hormone analogue); a sympathomimetic drug; an opioid; an analgesic such as a salicylate or a non-steroidal anti-inflammatory drug; an acetylcholinesterase inhibitor; an immunomodulatory; an NMDA receptor antagonist; a hypoglycaemic such as a sulphonylurea; a biguanide or a thiazolidinedione; a narcotic agonist or opiate antidote; a phosphodiesterase inhibitor such as a non-specific phosphodiesterase inhibitor or a phosphodiesterase type 3, type 4 or type 5 inhibitor; an antidepressant such as a tricyclic or tetracyclic antidepressant, a selective serotonin and noradrenaline reuptake inhibitor, a selective serotonin reuptake inhibitor, a selective noradrenaline reuptake inhibitor, a noradrenaline and selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a muscarinic antagonist or an azaspirone; a serotonin agonist; a serotonin antagonist; an adrenergic agonist; an adrenergic antagonist; an adrenergic neurone blocker; a benzodiazepine; a mucolytic agent; an antibiotic or antibacterial agent; an anti-fungal drug; an antiviral; a vaccine; an immunoglobulin; a local anaesthetic; an anticonvulsant; an angiotensin converting enzyme inhibitor; an angiotension II receptor blocker; a calcium channel blocker; an alpha-blocker; an antiarrhythmic; an anti-clotting agent; a potassium channel modulator; a cholesterol-lowering drug; a diuretic; a smoking cessation drug; a bisphosphonate; a dopamine agonist; a nucleic-acid medicine; an antipsychotic; and pharmaceutically acceptable salts or derivatives thereof. 
     
     
         44 . A medical device for delivering a pharmaceutical formulation in aerosol or spray form, comprising a pharmaceutical formulation as claimed in  claim 1 . 
     
     
         45 . A method of treating a patient comprising administering a therapeutically or prophylactically effective amount of formulation as claimed in  claim 1 , to said patient. 
     
     
         46 . A can, suitable for use in a pMDI device, containing a pharmaceutical formulation as claimed in  claim 1 . 
     
     
         47 . A can as claimed in  claim 46 , further comprising a metering valve. 
     
     
         48 . A method as claimed in  claim 15 , wherein the ratio of the MMAD of the dispersing agent particles to the MMAD of the pharmaceutically active agent particles is 1:20 or more. 
     
     
         49 . A method as claimed in  claim 15 , wherein the ratio of the MMAD of the dispersing agent particles to the MMAD of the pharmaceutically active agent particles is 1:100 or more. 
     
     
         50 . The method of  claim 45  further comprising using a device as claimed in  claim 44 .